Co-administration of steroids and zoledronic acid to prevent and treat osteoarthritis

ABSTRACT

A combination therapy for treating osteoarthritis is disclosed. The combination therapy includes the co-administration of a steroid and Zoledronic Acid. The coadministration of a steroid decreases the production of cytokines, and, therefore, decreases the pro-inflammatory effects of Zoledronic Acid. The co-administration of Zoledronic Acid with steroids treats osteoarthritis, and helps to prevent the onset of osteoarthritis in patients at risk for osteoarthritis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part under 35 USC 120 of U.S.patent application Ser. No. 13/791,685, filed Mar. 8, 2013. Thedisclosure of U.S. patent application Ser. No. 13/791,685 is herebyincorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to the method of use for theco-administration of steroids and Zoledronic Acid to prevent and treatosteoarthritis (“OA”). The steroid administration can be oral,parenteral, inhalational, or by suppository. The invention also patentsa composition of matter whereby 7.5 mg of Methyl Prednisolone is mixedwith 4 or 5 mg of Zoledronic Acid and infused in normal saline.

BACKGROUND OF THE INVENTION

Zoledronic Acid, sold as Zometa/Aclasta/Reclast, is a nitrogencontaining bisphosphonate that is used for treatment of hypercalcemia ofmalignancy, for the treatment of bone metastasis associated withmalignancies such as prostate and breast cancer, for the prevention ofand treatment of osteoporosis and for the treatment of Paget's disease.Zoledronic Acid is administered by an intravenous infusion of 4 mg every3-4 weeks (Zometa) for multiple myeloma and bone metastasis of othermalignancies or 5 mg once a year (Aclasta/Reclast) for non-oncologycindications. It is also used for the treatment of hypercalcemia ofmalignancy as needed.

Administration of Zoledronic Acid is complicated by what is described as“post-dosing syndrome” (PDS) which affects as much as 44% of patients asdescribed in the Zometa Prescribing Information(http://www.pharma.us.novartis.com/product/pi/pdf/Zometa.pdf). Thesyndrome is characterized by fever, nausea, bone pain, arthralgia,myalgia, chills, etc. In addition, administration of Zoledronic Acidleads to worsening of arthralgia in persons suffering fromosteoarthritis as described in Aclasta/Reclast/Zometa PrescribingInformation. The etiology of this phenomenon has not been identified,but is associated with an increase in levels of tumor necrosis factor(TNF), interleukin 6 (IL-6), and gamma interferon (γ IFN) (Dicuonzo G etal 2003, Schweitzer D H et al 1995, Thiebaud D et al 1997). Thesecytokines are usually produced by T cells. Zoledronic acid can causestimulation of a subset of T cells known as gamma delta (γ δ) T cells(Mariani S et al 2005). These cells, specifically V γ 9/V γ 2 T cells,can constitute up to 10% of circulating CD3 T cells when stimulated.Upon stimulation by Zoledronic Acid, these γ 6 T cells produceinterleukin 2 (IL-2) and TNF. IL-2 in turn can stimulate the productionof other cytokines such as IL-6 and γ IFN. Thus, treatment withZoledronic Acid can stimulate a subset of T cells that may lead topost-dosing syndrome by production and release of pro-inflammatorycytokines.

It would be advantageous to have compositions and methods for avoidingthe onset of post-dosing syndrome. The present invention provides suchcompositions and methods.

Osteoarthritis (OA) is the most common bone and joint disease influencedby genetic and environmental factors. Osteoarthritis is a debilitatingdisorder, affecting millions of patients a year. Many therapeutics usedto treat osteoarthritis have to be given on a daily basis, and in somecases, many times a day, in order to provide relief. The continuedadministration of these therapeutic agents, including non-steroidalanti-inflammatory drugs (NSAIDS), can result in liver disorders andgastro-intestinal perforations over time. In addition, they can causeimpairment of renal function. Other measures to treat OA include directinjection into the knee joint of hyaluronic acid which causes relief forthree to six months. It cannot be used in any other joint except theknee joint. Intra-articular steroids are used to treat OA, but they havea transient effect and are ineffective when given by any route otherthan by the intra-articular route. Thus, oral, intravenous, rectal,inhaled and topical steroids are not useful for treatment of OA. Allintra-articular therapies have the side effect of pain during injectionand possibilities of joint infection. All these medications treat pain,but do not have any effect on the disease. Thus, there is no diseasemodifying agent to treat OA. It would be advantageous to provideadditional treatments for osteoarthritis, which can be given lessfrequently, have fewer side effects, and be effective. Finally, adisease modifying drug would be very useful. In addition to thosepatients identified as suffering from osteoarthritis, there are alsopatients that are at a high risk of osteoarthritis. There are acceptedmedical tests to identify such patients. For example, associationstudies have uncovered the genetic factors behind OA, its susceptibilitygenes, which enables physicians to predict disease occurrence based ongenotype information. The predictive assays can screen for a singlesusceptibility gene, or, more preferably, a combination ofsusceptibility genes. However, there are few available preventativetreatments for patients at risk of developing osteoarthritis.

It would further be advantageous to provide compositions and methods forpreventing the onset of osteoarthritis in patients identified as beingat risk of developing osteoarthritis.

The present invention provides such compositions and methods.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to theco-administration of steroids and Zoledronic Acid to prevent or treatosteoarthritis. The steroids can be administered in oral (provided as agel, capsule, tablet, powder, liquid, or other pharmaceuticallyacceptable form), intravenous, intramuscular, or inhaled form, as asuppository, or injected directly into a joint.

The co-administration of a steroid decreases the production of cytokinesdescribed above, and, therefore, decreases the pro-inflammatory effectsof Zoledronic Acid. The co-administration of Zoledronic Acid withsteroids treats osteoarthritis, and helps to prevent the onset ofosteoarthritis in patients at risk for osteoarthritis. Existingosteoarthritis treatments are given frequently, for example, daily, orseveral times a day. In contrast, this combination can be given yearly,semi-yearly, quarterly, or monthly.

DETAILED DESCRIPTION

Compositions and methods for treating and preventing osteoarthritis aredescribed. The compositions comprise Zoledronic acid and a steroid.

Zoledronic Acid

Zoledronic acid has the following formula:

Zoledronic Acid is often administered as the bisphosphate, and can beadministered in the form of a pharmaceutically-acceptable salt.

Analogs of Zoledronic acid are disclosed, for example, in U.S. Pat. No.4,939,130, and these analogs are also intended to be within the scope ofthe invention, and can be used in place of Zoledronic Acid in eachembodiment of the invention described herein. These analogs generallyhave the formula:

wherein R₁ is a 5-membered heteroaryl radical which contains, as heteroatoms, 2 to 4 N-atoms or 1 or 2 N-atoms as well as 1 O- or S-atom, andwhich is unsubstituted or C-substituted by lower alkyl, phenyl or phenylwhich is substituted by lower alkyl, lower alkoxy and/or halogen, or bylower alkoxy, hydroxy, di-lower alkylamino, lower alkylthio and/orhalogen, and/or is N-substituted at a N-atom which is capable ofsubstitution by lower alkyl, lower alkoxy and/or halogen, and R₂ ishydrogen, hydroxy, amino, lower alkylthio or halogen.

Examples of 5-membered heteroaryl radicals containing 2 to 4 N-atoms or1 or 2 N-atoms as well as 1 O- or S-atom as hetero atoms are:imidazolyl, e.g. imidazol-1-yl, imidazol-2-yl or imidazol-4-yl,pyrazolyl, e.g. pyrazol-1-yl or pyrazol-3-yl, thiazolyl, e.g.thiazol-2-yl or thiazol-4-yl, or, less preferably, oxazolyl, e.g.oxazol-2-yl or oxazol-4-yl, isoxazolyl, e.g. isooxazol-3-yl orisooxazol-4-yl, triazolyl, e.g. 1H-1,2,4-triazol-1-yl,4H-1,2,4-triazol-3-yl or 4H-1,2,4-triazol-4-yl or 2H-1,2,3-triazol-4-yl,tetrazolyl, e.g. tetrazol-5-yl, thiadiazolyl, e.g. 1,2,5-thiadazol-3-yl,and oxdiazolyl, e.g. 1,3,4-oxadiazol-2-yl. These radicals may containone or more identical or different, preferably one or two identical ordifferent, substituents selected from the group mentioned at the outset.

Radicals

R₁, unsubstituted or substituted as indicated, are e.g. imidazol-2-yl orimidazol-4-yl radicals which are unsubstituted or C-substituted byphenyl or phenyl which is substituted as indicated, or which are C- orN-substituted by C₁₋₄ alkyl, e.g. methyl, and are typicallyimidazol-2-yl, 1-C₁₋₄ alkylimidazol-2-yl such as 1-methylimidazol-2-yl,or 2- or 5-C₁₋₄ alkylimidazol-4-yl such as 2- or 5-methylimidazol-4-yl,unsubstituted thiazolyl radicals, e.g. thiazol-2-yl, or 1H-1,2,4-triazolradicals, unsubstituted or substituted by C₁₋₄ alkyl such as methyl,e.g. 1-C₁₋₄ alkyl-1H-1,2,4-triazol-5-yl such as1-methyl-1H-1,2,4-triazol-5-yl, or imidazol-1-yl, pyrazolyl-1-yl,1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl or tetrazol-1-yl radicals,unsubstituted or C-substituted by phenyl or phenyl which is substitutedas indicated or by C₁₋₄ alkyl such as methyl, for example imidazol-1-yl,2-, 4- or 5-C₁₋₄ alkylimidazol-1-yl such as 2-, 4- or5-methylimidazol-1-yl, pyrazol-1-yl, 3- or 4-C₁₋₄ alkylpyrazol-1-yl suchas 3- or 4-methylpyrazol-1-yl, 1H-1,2,4-tetrazol-1-yl, 3-C₁₋₄alkyl-1H-1,2,4-triazol-1-yl such as 3-methyl-1H-1,2,4-triazol-1-yl,4H-1,2,4-triazol-1-yl, 3-C₁₋₄ alkyl-4H-1,2,4-triazol-4-yl such as3-methyl-4H-1,2,4-triazol-4-yl or 1H-1,2,4-tetrazol-1-yl.

Radicals and compounds hereinafter qualified by the term “lower” will beunderstood as meaning typically those containing up to 7 carbon atomsinclusive, preferably up to 4 carbon atoms inclusive. The general termshave for example the following meanings:

Lower alkyl is for example C₁₋₄ alkyl such as methyl, ethyl, propyl orbutyl, and also isobutyl, sec-butyl or tert-butyl, and may further beC₅₋₇ alkyl such as pentyl, hexyl or heptyl.

Phenyl-lower alkyl is for example phenyl-C₁₋₄ alkyl, preferably1-phenyl-C₁₋₄ alkyl such as benzyl.

Lower alkoxy is for example C₁₋₄ alkoxy such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy.

Di-lower alkylamino is for example di-C₁₋₄ alkylamino such asdimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino,N-methyl-N-propylamino or dibutylamino.

Lower alkylthio is for example C₁₋₄ alkylthio such as methylthio,ethylthio, propylthio or butylthio, and also isobutylthio, sec-butylthioor tert-butylthio.

Halogen is for example halogen having an atomic number of up to 35inclusive, such as fluorine, chlorine or bromine.

Pharmaceutically acceptable salts of Zoledronic acid, or the othercompounds of Formula I, include in particular the salts thereof withpharmaceutically acceptable bases, such as non-toxic metal salts derivedfrom metals of groups Ia, Ib, IIa and IIb, e.g. alkali metal salts,preferably sodium or potassium salts, alkaline earth metal salts,preferably calcium or magnesium salts, copper, aluminium or zinc salts,and also ammonium salts with ammonia or organic amines or quaternaryammonium bases such as free or C-hydroxylated aliphatic amines,preferably mono-, di- or tri-lower alkylamines, e.g. methylamine,ethylamine, dimethylamine or diethylamine, mono-, di- ortri(hydroxy-lower alkyl)amines such as ethanolamine, diethanolamine ortriethanolamine, tris(hydroxymethyl)aminomethane or2-hydroxy-tert-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-loweralkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines such as2-(dimethylamino)ethanol or D-glucamine, or quaternary aliphaticammonium hydroxides, e.g. with tetrabutylammonium hydroxide.

Zoledronic Acid, as well as the other compounds of Formula I may also beobtained in the form of inner salts, provided the group R₁ issufficiently basic. These compounds can therefore also be converted intothe corresponding acid addition salts by treatment with a strong proticacid such as a hydrohalic acid, sulfuric acid, sulfonic acid, e.g.methanesulfonic acid or p-toluenesulfonic acid, or sulfamic acid, e.g.N-cyclohexylsulfamic acid.

In one embodiment, Zoledronic Acid is administered as approved by theFDA, that is, by infusion, typically in infusions of around 4 to 5 mginfusions, once a year, or once every two years for post-menopausalwomen. In another embodiment, Zoledronic Acid is administered morefrequently, for example, semi-yearly, quarterly, or monthly.

When administered as an infusion, the Zoledronic Acid is administered ina form suitable for intravenous administration to a human or otheranimal patient.

As used herein, “suitable for intravenous administration to a human orother animal patient” refers to an aqueous solution including rifalaziland one or more pharmaceutically acceptable excipients, such as salt,which forms a saline solution. Solutions that are suitable forintravenous administration to a human or other animal patient do notinclude excipients that would compromise the health of a patient. Forexample, certain organic solvents (e.g., dimethyl sulfoxide, ethanol,propanol, acetone, and dimethyl formamide) are miscible in water anduseful for the preparation of aqueous solutions of insoluble compounds.However, these organic solvents are poisonous at certain concentrations,so should not be administered intravenously to a patient at harmfulconcentrations. Furthermore, solutions that are suitable for intravenousadministration to a human typically have a pH of between 4 and 9.Accordingly, the solutions may be buffered as appropriate, for example,using phosphate-buffered saline.

By “infusion” is meant a continuous intravenous administration ofZoledronic Acid, or other compound of Formula I, or apharmaceutically-acceptable salt thereof, over a period of greater thanfive minutes, wherein the compounds are ideally administered at aconstant or near-constant rate.

In one aspect of this embodiment, patients are supplemented with calciumand/or vitamin D, if dietary intake is not sufficient. Whether or notsupplementation is desired can be readily determined by a physician.

In another aspect of this embodiment, to prevent glucocorticoid-inducedosteoporosis in patients expected to be on glucocorticoids for at least12 months, Zoledronic Acid is administered in a 5 mg intravenousinfusion once a year, given over no less than around 5 minutes,preferably no less than around 15 minutes. To prevent osteoporosis inpostmenopausal women, the Zoledronic Acid is administered in a 5 mgintravenous infusion given once every 2 years intravenously over no lessthan 15 minutes. Accordingly, the frequency of dosing can be once everytwo years for post-menopausal women. Patients must be adequatelysupplemented with calcium and vitamin D if dietary intake is notsufficient. Postmenopausal women require an average of 1200 mg calciumand 800 to 1000 International Units of vitamin D daily.

However, in other embodiments, the Zoledronic Acid is administered byinjection. Zoledronic Acid has a half-life (t1/2α) of about 0.24 hours,and its administration is known to be associated with certain sideeffects in a large subpopulation of patients. The co-administration ofsteroids helps to minimize or eliminate these side effects. By“co-administration,” it is meant that the steroids can be administeredwithin two hours before or after the Zoledronic acid, typically withinone hour before or after the Zoledronic acid, and, more typically, atthe same time, or within a half an hour before or after the ZoledronicAcid.

Steroids

Suitable steroids include, for example, hydrocortisone, hydrocortisoneacetate, cortisone acetate, tixocortol pivalate, prednisolone,methylprednisolone, prednisone, triamcinolone acetonide, triamcinolonealcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide,fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodiumphosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone,hydrocortisone-17-valerate, acleometasone dipropionate, betamethasonevalerate, betamethasone dippropionate, prednicarbate,clobetasone-17-butyrate, clobetasol-17-propionate, fluocortilonecaproate, fluocortolone pivalate, and fluprednidene acetate,hydrocortisone-17-butyrate, 17-aceponate, 17-buteprate, andprednicarbate. The appropriate dose of steroid that is administered canbe readily determined by one of skill in the art, for example, atreating physician. However, in one embodiment, the dose of steroidsdoes not exceed the equivalent of 50 mg of prednisolone, and is not lessthan the equivalent of 5 mg of prednisone. The steroids can be givenorally (for example, 7.5 mg of Prednisone), by a separate infusion (forexample, 7.5 mg of Methyl Prednisolone), mixed in with Zoledronic Acidin the same infusion, or be administered intramuscularly,subcutaneously, by rectal suppository, by inhalation, or injecteddirectly into a joint.

When considering a steroid to administer with the Zoledronic Acid orother compound of Formula I, or pharmaceutically-acceptable saltthereof, it is useful to note which are suitable for oraladministration, and which are suitable for injection (whetherintramuscular (IM) or intravenous (IV). The following table lists whichsteroids are suitable for oral administration and/or injection.

TABLE 1 Injectable Steroid Oral (IM/IV) Hydrocortisone Y YHydrocortisone acetate Y Y Cortisone acetate Y N Tixocortol pivalateT YN Prednisolone Y N Methylprednisolone Y Y Prednisone Y N Triamcinoloneacetonide Y Y triamcinolone alcohol Y Y mometasone N N Amcinonide N NBudesonide Y N Desonide n N fluocinonide n N fluocinolone acetonide N NHalcinonide N N Betamethasone Y Y Betamethasone sodium N Y phosphateDexamethasone Y Y Dexamethasone sodium N N phosphate Fluocortolone N NHydrocortisone-17-valerate N N Aclometasone dipropionate N NBetamethasone valerate N N Betamethasone N N dippropionate PrednicarbateN N Clobetasone-17-butyrate N N Clobetasol-17-propionate N NFluocortolone caproate N N Fluocortolone pivalate N N Fluprednideneacetate ? ? Hydrocortisone-17- N N butyrate 17-aceponate ? ?17-buteprate N N prednicarbate N N

Additional Therapeutic Agents

Additional therapeutic agents can be administered with the steroid andZoledronic Acid. For example, analgesics and anesthetics can beadministered. The anesthetic is any compound that is capable of blockingnerve impulses from the area of discomfort to the brain. Representativeanesthetics include local anesthetics such as marcaine, procaine(novocaine), chloroprocaine (nesacaine), cocaine, lidocaine, tetracaine(amethocaine, pontocaine), mepivacaine, etidocaine (duranest),bupivacaine (marcaine), dibucaine (cinchocaine, nupercaine), prilocalne(citanest), benzoxinate (dorsacaine), proparacaine (alcaine, opthaineand opthetic), benzocaine (anesthesin), butamben (butesin),oxybuprocaine, pramoxine, proxymetacaine, and Alpha-2 adrenergicreceptor agonists such as Dexmedetomidine and Propofol.

The choice of anesthetic will depend on the type of discomfort to bealleviated and is generally known to those skilled in the art ofanesthesia. For example, lidocaine and marcaine are commonly injected,along with cortisone or hydrocortisone, directly into joints.

In addition to administration of additional therapeutic agents when theZoledronic acid is administered, a patient can supplement the treatmentby taking glycosaminoglycans, such as hyaluronic acid, glucosamine,chondroitin, and the like. These glycosaminoglycans are typicallyadministered in an oral formulation, such as a pill, tablet, capsule,and the like, and hyaluronic acid can be injected along with theZoledronic Acid, or pharmaceutically-acceptable salts thereof, and thesteroid, directly into the knee, shoulder (particularly, the rotatorcuff), the lumbar spine, and other joints, if desired.

Methods of Treatment

To treat a patient suffering from osteoarthritis, a patient can beadministered a combination of Zoledronic Acid and a steroid. To obtainthe maximum efficacy, the treatment should be initiated in patients withearly stages of osteoarthritis (“OA”) pathogenesis, or at least as earlyas possible.

The administration can be, for example, once a year. In one embodiment,the Zoledronic Acid and steroid are administered by simultaneousinjection.

In one aspect of this embodiment, 7.5 mg of Methyl Prednisolone can bedissolved with about 4 to about 5 mg of Zoledronic Acid in anappropriate vehicle for injection, such as Normal Saline or PhosphateBuffered Saline (up to 100 cc) by swirling gently in room temperaturefor one minute. This mixture is ideally used within 5 minutes of mixingif kept at room temperature, or within an hour if kept in arefrigerator, so as to minimize the possibility of having a precipitateform.

In another embodiment, a steroid is given orally or via inhalation, andthe Zoledronic Acid is given via infusion.

In another embodiment, a mixture of Zoledronic Acid or other compound ofFormula I and a steroid is directly injected into a joint, such as aknee, shoulder, or hip joint. In this embodiment, the Zoledronic Acidand steroid can be combined with an anesthetic, or an anesthetic can beadministered shortly before or after the combination of the ZoledronicAcid and steroid.

Representative anesthetics for this embodiment include lidocaine andmarcaine

Representative steroids for this embodiment include cortisone,hydrocortisone, and pharmaceutically acceptable salts thereof.

Methods for Predicting the Onset of Osteoarthritis

The methods described herein for treating osteoarthritis can also beused to prevent the onset of osteoarthritis for patients at risk ofdeveloping osteoarthritis.

To obtain the maximum efficacy, treatment should ideally be initiatedwhen the patient is early stages of OA pathogenesis (see, for example,Yu et al., “Efficacy of zoledronic acid in treatment of osteoarthritisis dependent on the disease progression stage in rat medial meniscaltear model,” Acta Pharmacol Sin. 2012 July; 33(7):924-34). Accordingly,it can be useful to identify patients at risk of developingosteoarthritis, and minimize the damage to their joints.

Numerous methods are described in the literature for predictingosteoarthritis, in man and in other mammals. These methods include, forexample, assessments of joint mobility, and genetic testing using knownalleles predictive of osteoarthritis. For example, methods forpredicting osteoarthritis of the hip in Labrador retrievers are taughtin Corfield, et al., “Assessment of the hip reduction angle forpredicting osteoarthritis of the hip in the Labrador Retriever,” AustVet J. 2007 June; 85(6):212-6. Methods for predicting osteoarthritis ofthe hip in humans are taught, for example, in Birrell et al.,“Predicting radiographic hip osteoarthritis from range of movement,”Oxford Journals Medicine Rheumatology, Volume 40, Issue 5 Pp. 506-512.Restriction in range of movement was predictive of the presence of OA innew presenters to primary care with hip pain, and the results of thisexamination can be used to inform decisions regarding treatment with themethods described herein.

Methods for predicting osteoarthritis of the knee are described, forexample, in Takahashi et al., “Prediction model for knee osteoarthritisbased on genetic and clinical information,” Arthritis Research & Therapy2010, 12:R187. Osteoarthritis (OA) is the most common bone and jointdisease influenced by genetic and environmental factors. Recentassociation studies have uncovered the genetic factors behind OA, itssusceptibility genes, which enable one to predict disease occurrencebased on genotype information. The prediction can be based on theeffects of only a single susceptibility gene, or using OA-predictionmodels based on more than one gene. Risk alleles that can be assessedinclude the three susceptibility genes, asporin (ASPN), growthdifferentiation factor 5 (GDF5), and double von Willebrand factor Adomains (DVWA). Clinical information, as well as the number of riskalleles, can be used for OA prediction.

The present invention will be better understood with reference to thefollowing non-limiting examples.

EXAMPLE 1 Treatment of Osteoporosis Patients with Zoledronic Acid andSteroids

Eight patients with osteoporosis were treated with a single infusion ofZoledronic Acid alone (four patients) or with a single infusion of thecombination of prednisone and Zoledronic Acid (ZP, four patients). Allfour patients who received Zoledronic Acid suffered from PDS. Incontrast, none of the patients receiving ZP suffered from PDS.

Of the 8 subjects, five had osteoarthritis. Of these five, three weretreated with ZP and two with Zoledronic Acid. All three subjects treatedwith ZP had a decrease in joint pain (VAS scale) six months after thesingle infusion and one subject up to one year after the singleinfusion. In the Zoledronic Acid arm, both subjects had the same (one)or worse (one) level of pain than before the single infusion.

In a further study, this one, a single blind, single center study, 20subjects with knee osteoarthritis were randomized to either intravenousZP or ZA in a 1:1 ratio. Subjects were followed for six months. Efficacywas measured by change in pain in 100 mm visual analogue score (VAS)from baseline (mean values). Patients were asked about the level of painwithout taking rescue medications (NSAIDS or tramadol). Bone mineraldensity (BMD) was determined at baseline and six months to detect anyeffect on bone.

The results are shown in Table 2 below:

TABLE 2 PDS(# Cohort reporting/total) ΔBMD Δ Mean VAS ZA 6/10 0 −10 mmZP 0/10 0 −40 mm

ZP was clearly more effective in controlling OA pain than ZA alone, withthe added benefit of no post-dosing symptoms. The efficacy could nothave been the result of Prednisolone, since IV Prednisolone by itselfhas no effect on arthritis pain, which is why steroids are not givenorally or intravenously for osteoarthritis (only intra-articularly²).

In addition, the effect of Prednisolone is transient, less than a day,and so cannot account for the analgesic effect six months out. Theeffect of ZA was similar to that seen in the earlier study.

REFERENCES

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The contents of all references described herein are incorporated hereinby reference in their entirety for all purposes.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. Therefore, it is to be understood that the foregoing isillustrative of the present invention and is not to be construed aslimited to the specific embodiments disclosed, and that modifications tothe disclosed embodiments, as well as other embodiments, are intended tobe included within the scope of the appended claims. The invention isdefined by the following claims, with equivalents of the claims to beincluded therein.

What is claimed:
 1. A method for treating osteoarthritis in a patient inneed thereof, the method comprising intravenous administration to thepatient a combination of prednisolone or a pharmaceutically acceptablesalt thereof and Zoledronic acid or a pharmaceutically acceptable saltthereof in a single infusion.
 2. The method of claim 1, wherein themethod involves treating a patient suffering from osteoarthritis.
 3. Themethod of claim 1, wherein the dose is between 5 mg and 50 mg ofprednisolone.